TY - JOUR
T1 - Antidepressant Potential of (<em>R</em>)-Ketamine in Rodent Models: Comparison with (<em>S</em>)-Ketamine
JF - Journal of Pharmacology and Experimental Therapeutics
JO - J Pharmacol Exp Ther
SP - 9
LP - 16
DO - 10.1124/jpet.116.239228
VL - 361
IS - 1
AU - Fukumoto, Kenichi
AU - Toki, Hidetoh
AU - Iijima, Michihiko
AU - Hashihayata, Takashi
AU - Yamaguchi, Jun-ichi
AU - Hashimoto, Kenji
AU - Chaki, Shigeyuki
Y1 - 2017/04/01
UR - http://jpet.aspetjournals.org/content/361/1/9.abstract
N2 - The rapid-acting and long-lasting antidepressant effects of (R,S)-ketamine have recently gained much attention. Although (S)-ketamine has been studied as an active isomer, recent evidence suggests that (R)-ketamine exhibits longer-lasting antidepressant effects than (S)-ketamine in rodents. However, the antidepressant potential of (R)-ketamine has not been fully addressed. In the present study, we compared the antidepressant effects of (R)-ketamine with those of (S)-ketamine in animal models of depression, including a model that is refractory to current medications. Both (R)-ketamine and (S)-ketamine exhibited antidepressant effects at 30 minutes as well as at 24 hours after administration in forced-swimming and tail-suspension tests in mice. At 48 hours after administration, however, (R)-ketamine still exerted a significant antidepressant effect in the tail-suspension test, whereas the effect of (S)-ketamine was no longer observed. Moreover, (R)-ketamine, but not (S)-ketamine, significantly reversed the depressive-like behavior induced by repeated treatments with corticosterone in rats at 24 hours after a single administration. This effect was attenuated by an α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist, suggesting the involvement of AMPA receptor stimulation in the effects. Both (R)-ketamine and (S)-ketamine exhibited practically the same exposure levels in plasma, brain, and cerebrospinal fluid in mice and rats, and both compounds were rapidly eliminated from plasma (&lt;4–8 hours). The present results confirmed the previous findings that (R)-ketamine exerted longer-lasting antidepressant effects than (S)-ketamine in animal models of depression. Moreover, our study is the first to demonstrate that (R)-ketamine exerted a sustained antidepressant effect even in a model that is refractory to currently prescribed antidepressants.
ER -